Transition metal complexes are often prodrugs which undergo activation by ligand exchange and redox reactions before they interact with target sites. It is therefore important to understand the roles of both the metal and the ligands in their activation, especially in cells. Here we use a combination of synchrotron nanoprobe X-ray fluorescence (XRF) from Os L3M5 and Br KL3 emissions and inductively coupled plasma-mass spectrometry (ICP-MS) detection of 189Os, 79Br, and 127I, to investigate the time-dependent accumulation and localization of osmium as well as the monodentate ligand and the chelated phenylazopyridine in A2780 human ovarian cancer cells treated with the potent anticancer complexes [Os(η6-p-cymene)(4-R2-phenyl-azopyridine-5-R1)X]PF6, with R2 = NMe2 or OH, R1 = H or Br, and X = Cl or I. The data confirm that the relatively inert iodido complexes are activated rapidly in cancer cells by release of the iodido ligand, probably initiated by attack by the intracellular tripeptide glutathione (γ-L-Glu-l-Cys-Gly) on the azo double bond. The bond between osmium and the azopyridine appears to remain stable in cells for ca. 24 h, although some release of the chelated ligand is observed. Interestingly, the complexes seem to be degraded more rapidly in normal human cells, perhaps providing a possible mechanism for selective cytotoxicity towards cancer cells.
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We thank the Engineering and Physical Sciences Research Council (EPSRC grant no. EP/P030572/1) and Anglo American Platinum for funding. We thank Diamond Light Source and Warwick Collaborative Postgraduate Research Scholarships for a PhD studentship for E. M. B. We thank L. Song for assistance with ICP-MS experiments. C.S.C. thanks Gipuzkoa Foru Aldundia (Gipuzkoa Fellows program; grant number 2019-FELL-000018-01/62/2019) for financial support. This work was performed under the Maria de Maeztu Units of Excellence Programme – Grant No. MDM-2017-0720 Ministry of Science, Innovation and Universities. All synchrotron work was performed at the I14 Beamline (DLS, Oxford) under experiment numbers MG-19838 and SP-20548. We thank S. E. Bakker and I. Hands-Portsman (Advanced Bioimaging RTP) for assistance and training in plunge-freezing, and J. Tod for assistance with freeze-drying. We thank J. Parker and F. Cacho-Nerin for assistance during the experiments at the I14 Beamline.
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ASJC Scopus subject areas
- Inorganic Chemistry